Deprenyl (also referred to herein as selegiline or R-((-)-N,.alpha.-Dimethyl-N-2-propynyl phenethylamine) was first used as an adjunct to conventional drug therapy (L-dihydroxyphenylalanine (L-DOPA) plus a peripheral decarboxylase inhibitor) of Parkinson's disease (PD) in Europe over a decade ago on the basis that as a selective monoamine oxidase-B (MAO-B) inhibitor, it would elevate brain dopamine levels and potentiate the pharmacologic action of dopamine formed from L-DOPA, and yet prevent the tyramine-pressor effect observed with non-selective MAO inhibitors. The combined drug therapy was reported to prolong the anti-akinetic effects of L-DOPA, resulting in the disappearance of on-off effects, reduced functional disability, and increased life-expectancy in PD patients (Bernheimer, H., et al., J. Neurolog. Sci., 1973.20: p. 415-455,.Birkmayer, W., et al., J. Neural Transm., 1975. 36: p. 303-336, Birkmayer, W., et al., Mod. Prob. pharmacopsychiatr., 1983. 19: p. 170-177, Birkmayer, W. and P. Riederer, Hassler, R. G. and J. F. Christ (Ed.) Advances In Neurology, 1984. 40(Y): p.0-89004, and Birkmayer, W., et al., J. Neural Transm., 1985. 64(2): p. 113-128).
Studies examining deprenyl as an adjunct to conventional L-DOPA therapy have reported a short term benefit which was usually lost by 1 year or less. Some, but not all, have reported that the levodopa dose can be decreased when taken in conjunction with deprenyl (Elizan, T. S., et al., Arch Neurol, 1989. 46(12): p. 1280-1283, Fischer, P. A. and H. Baas, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Golbe, L.I., Neurology, 1989. 39:p. 1109-1111, Lieberman, A. N. et al., N.Y. State J. Med., 1987. 87: p. 646-649, Poewe, W., F. Gerstenbrand, and G. Ransomayr, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Cedarbaum, J. M., M. Hoey, and F. H. McDowell, J. Neurol Neurosurg Psychiatry, 1989. 52(2): p. 207-212, and Golbe, L. I., J. W. Langston, and I. Shoulson, Drugs, 1990.39(5): p. 646-651).
Increasingly deprenyl is being administered to Parkinson's disease patients following reports (parkinson, S. G. Arch Neurol 46, 1052-1060 (1989) and U.S.A., P.S.G. N. Engl. J. Med. 321, 1364-1371 (1989)) that it delays the disease's progression; however, no satisfactory mechanism has been proposed to explain its action.
Support for the use of deprenyl in Parkinson's disease (PD) is largely based on the findings of the DATATOP project (Parkinson, S. G. Arch Neurol 46, 1052-1060 (1989) and U.S.A., P.S.G.N. Engl. J. Med. 321, 1364-1371 (1989)). This multicentre study reported that deprenyl delays the onset of disabling symptoms requiring additional pharmacotherapy by nearly one year; these. findings were reproduced in an independent but smaller study (Tetrud, J. W. & Langston, J. W. Science 245, 519-522 (1989)). Unfortunately, the design of the DATATOP study and its conclusions have come under strong criticism (Landau, W.M. Neurology 40, 1337-1339 (1990). Furthermore, while the authors of these projects state that their results are consistent with the hypothesis that deprenyl slows the progression of PD (Parkinson, S. G. Arch Neurol 46, 1052-1060 (1989), U.S.A., P.S.G. N. Engl. J. Med. 321, 1364-1371 (1989) and Tetrud, J. W. & Langston, J. W. Science 249, 303-304 (1990)), "they by no means constitute proof" (Tetrud, J. W. & Langston, J. W. Science 249, 303-304 (1990)).
It has been proposed that deprenyl, an MAO-B inhibitor, may delay the progression of PD by minimizing free-radical induced death of surviving dopaminergic nigrostriatal (DNS) neurons (Langston, J. W. in Parkinson's Disease and Movement Disorders (eds. Jankovic, J. & Tolosa, E.) 75-85 (Urban and Schwarzenberg, Baltimore-Munich 1988)) based on the observation that deprenyl could block MPTP-induced neurotoxicity in primates (Langston, J. W., Forno, L. S. Robert, C. S. & Irwin, I. Brain Res 292, 390-394 (1984)) and the hypothesis that other environmental toxins with mechanisms of action similar to that of MPTP may be involved in the etiology of PD (Tanner, C. M. TINS 12, 49-54 (1989)). However, since MAO-B is not present in dopaminergic neurons (Vincent, S. R. Neuroscience 28, 189-199 (1989), Pintari, J. E., et al. Brain Res 276, 127-140 (1983), Westlund, K. N., Denney, R. M., Kochersperger, L. M., Rose, R. M. & Abell, C. W. Science (Wash D.C.) 230, 181-183 (1985) and Westlund, K. N., Denney, R. M., Rose, R. M. & Abell, C. W. Neuroscience 25, 439-456 (1988)), it is unclear how its inhibition would protect DNS neurons unless another highly toxic compound were formed in non-dopaminergic neurons which could in turn damage DNS neurons in a manner analogous to that of MPTP. Surprisingly, no investigation has included the measurement of DNS neuronal numbers to determine whether deprenyl could influence neuronal survival when measured after MPTP has been cleared from the central nervous system.